Most human and animal pathogens including those that cause tuberculosis (TB), initiate infection via the mucosal surfaces. Accordingly, protective immunity against such pathogens may require induction of strong mucosal immune responses. However, mucosal immune responses are generally weak following parenteral immunization. Despite the obvious need for vaccines, particularly TB vaccines, to protect against mucosal sites, the vaccines in use today are given by intradermal or subcutaneous injection. The development of more effective compositions, and/or delivery systems for vaccines by alternate routes is therefore desirable. Oral administration of vaccines in particular has a number of advantages including ease of administration and targeting of the mucosal immune response. Despite this, oral vaccination of animals and man to provide mucosal and/or systemic immunity has to date been largely ineffective. Efficacy of such vaccines has been hampered by degradation of the vaccine as it passes through the gut. In particular, most antigenic compounds possess peptide bonds that are readily broken down by gastric and proteolytic enzymes in the gut.
A number of vaccines rely on the use of freeze-dried preparations of organisms. For example, the current vaccine for human TB is based on freeze-dried preparations of a live attenuated bacterium called Bacille Calmette Guerin (BCG). However, it has been shown that freeze-drying procedures result in 30 to 50% loss of viability of BCG and impaired recovery of remaining live bacteria (7). A composition which retains greater viability of organisms prior to use would contribute greatly to the effectiveness of such vaccines.
To improve immune responses, antigens have been mixed with a number of adjuvant substances to stimulate immunogenicity. These adjuvants are primarily alum and oil-in-water emulsions. The latter group is typified by the Freund's mineral oil adjuvants. However, the use of Freund's complete adjuvant (FCA) in human and veterinary vaccines is contraindicated because of toxic reactions that have been reported. For these reasons, Freund's adjuvant may also be unsuitable for oral administration.
In other oil-in-water emulsions surfactants have been required because of the high oil content. Detergent properties of surfactants render them unsuitable for parenteral or oral administration. Further, toxic reactions even for approved surfactants have been reported. A further drawback with emulsions are that they are heterogeneous systems of one immiscible liquid dispersed in another. This is unstable and results in separation of the aqueous phase over time. This poses difficulties for maintaining vaccines in stable suspension. Moreover, antigens trapped in the aqueous phase of water-in-oil emulsions are unlikely to be protected from degradation in the stomach.
Liposomes and lipid vesicles have also been explored for use with vaccines, particularly with small antigenic components that may be readily encapsulated. Generally, liposomes and vesicles are not useful for encapsulation of large antigens such as live microorganisms. Moreover, liposomes and vesicles are costly and time consuming to produce, and the extraction procedures used in their preparation may result in alteration of the chemical structure or viability of vaccine preparations and hence their immunogenicity. For example, heat and solvents may alter the biological integrity of antigenic components such as proteins.
It is therefore an object of the present invention to provide an immunogenic composition and/or delivery system which addresses these desiderata or which at least provides the public with a useful choice.